Modulation of activation-induced T cell death by phosphodiesterase 4B2, a therapeutic target for T cell neoplasias

J. Arp, PhD, M. L. Baroja, PhD, S. H. Nazarian, BSc, T. A. Chau, C. A. Strathdee, PhD, J. Madrenas, MD, PhD.

Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada N6A 5K8

Phosphodiesterases (PDEs) are a large group of enzymes, grouped in at least 11 families, that degrade cAMP. Although PDE activity is required for T cell activation, their precise role in this process is unknown. In addition, scattered evidence suggests that PDEs, in particular PDE4, may be good targets for the development of drugs aimed at inducing death of neoplastic T cells. Since we have previously shown that the B2 isoform of PDE4B associates with the CD3 e chain of the antigen receptor of T lymphocytes (TCR) and is selectively phosphorylated upon TCR ligation, we examined whether this isoform regulates T cell responsiveness and ensuing activation-induced T cell death. We generated a panel of T cell clones that lack expression of endogenous PDE4B isoforms but have been retrovirally transduced with a recombinant PDE4B2-green fluorescence Protein (gfp) cDNA fusion. Using this system, we have found that expression of PDE4B2 is under post-transcriptional regulation through a mechanism that involves PDE4 phosphodiesterase activity. Using confocal microscopy, we have seen that PDE4B2-gfp is distributed peripherally, close to the plasma membrane of T cells consistent with its association with the TCR complex. More importantly, expression of PDE4B2 in T cells is associated with a significant increase in T cell responsiveness to superantigen stimulation and subsequent activation-induced T cell death. Our data indicate that the PDE4B2 isoform is involved in the modulation of T cell responsiveness and may be a good target of therapies aimed at inducing clonal activation-induced T cell death in lymphoid neoplasias.

KEY WORDS: Immunotherapy, T cell, Lymphoid Neoplasias, Phosphodiesterases, cAMP.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Chromosomal Aberrations.